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- PDB-5qu0: TGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH 6-... -

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Basic information

Entry
Database: PDB / ID: 5qu0
TitleTGF-BETA RECEPTOR TYPE 1 KINASE DOMAIN (T204D) IN COMPLEX WITH 6-[4-(3-CHLORO-4-FLUOROPHENYL)-1-(2-HYDROXYETHYL)-1H-IMIDAZOL-5-YL]IMIDAZO[1,2-B]PYRIDAZINE-3-CARBONITRILE
ComponentsTGF-beta receptor type-1
KeywordsTRANSFERASE / ALK5 / KINASE DOMAIN / TRANSFERASE-TRANSFERASE INHIBITOR COMPLEX
Function / homology
Function and homology information


extracellular structure organization / epicardium morphogenesis / parathyroid gland development / transforming growth factor beta ligand-receptor complex / regulation of cardiac muscle cell proliferation / myofibroblast differentiation / positive regulation of tight junction disassembly / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / TGFBR2 Kinase Domain Mutants in Cancer / transforming growth factor beta receptor activity ...extracellular structure organization / epicardium morphogenesis / parathyroid gland development / transforming growth factor beta ligand-receptor complex / regulation of cardiac muscle cell proliferation / myofibroblast differentiation / positive regulation of tight junction disassembly / positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation / TGFBR2 Kinase Domain Mutants in Cancer / transforming growth factor beta receptor activity / positive regulation of mesenchymal stem cell proliferation / ventricular compact myocardium morphogenesis / SMAD2/3 Phosphorylation Motif Mutants in Cancer / TGFBR1 KD Mutants in Cancer / positive regulation of vasculature development / regulation of epithelial to mesenchymal transition / activin receptor activity, type I / cardiac epithelial to mesenchymal transition / transforming growth factor beta receptor activity, type I / activin receptor complex / mesenchymal cell differentiation / neuron fate commitment / germ cell migration / positive regulation of extracellular matrix assembly / type II transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / angiogenesis involved in coronary vascular morphogenesis / receptor protein serine/threonine kinase / transmembrane receptor protein serine/threonine kinase activity / pharyngeal system development / activin binding / coronary artery morphogenesis / activin receptor signaling pathway / filopodium assembly / ventricular trabecula myocardium morphogenesis / transforming growth factor beta binding / embryonic cranial skeleton morphogenesis / response to cholesterol / I-SMAD binding / negative regulation of chondrocyte differentiation / collagen fibril organization / endothelial cell proliferation / endothelial cell activation / skeletal system morphogenesis / lens development in camera-type eye / positive regulation of filopodium assembly / anterior/posterior pattern specification / artery morphogenesis / ventricular septum morphogenesis / roof of mouth development / TGF-beta receptor signaling activates SMADs / SMAD binding / negative regulation of endothelial cell proliferation / positive regulation of SMAD protein signal transduction / blastocyst development / regulation of protein ubiquitination / endothelial cell migration / bicellular tight junction / epithelial to mesenchymal transition / positive regulation of epithelial to mesenchymal transition / positive regulation of apoptotic signaling pathway / positive regulation of stress fiber assembly / cellular response to transforming growth factor beta stimulus / positive regulation of endothelial cell proliferation / Downregulation of TGF-beta receptor signaling / post-embryonic development / transforming growth factor beta receptor signaling pathway / negative regulation of cell migration / thymus development / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / kidney development / skeletal system development / cell motility / negative regulation of extrinsic apoptotic signaling pathway / wound healing / cellular response to growth factor stimulus / male gonad development / UCH proteinases / nervous system development / heart development / positive regulation of cell growth / regulation of gene expression / peptidyl-serine phosphorylation / in utero embryonic development / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / regulation of cell cycle / Ub-specific processing proteases / endosome / protein kinase activity / intracellular signal transduction / positive regulation of cell migration / membrane raft / protein serine/threonine kinase activity / apoptotic process / ubiquitin protein ligase binding / positive regulation of cell population proliferation / positive regulation of gene expression / regulation of DNA-templated transcription / positive regulation of DNA-templated transcription
Similarity search - Function
GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / Activin types I and II receptor domain / Activin types I and II receptor domain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 ...GS domain / Transforming growth factor beta type I GS-motif / GS domain profile. / GS motif / Activin types I and II receptor domain / Activin types I and II receptor domain / Ser/Thr protein kinase, TGFB receptor / Snake toxin-like superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-QMV / TGF-beta receptor type-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.67 Å
AuthorsSheriff, S.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGF beta R1 Inhibitor as an Immuno-oncology Agent.
Authors: Velaparthi, U. / Darne, C.P. / Warrier, J. / Liu, P. / Rahaman, H. / Augustine-Rauch, K. / Parrish, K. / Yang, Z. / Swanson, J. / Brown, J. / Dhar, G. / Anandam, A. / Holenarsipur, V.K. / ...Authors: Velaparthi, U. / Darne, C.P. / Warrier, J. / Liu, P. / Rahaman, H. / Augustine-Rauch, K. / Parrish, K. / Yang, Z. / Swanson, J. / Brown, J. / Dhar, G. / Anandam, A. / Holenarsipur, V.K. / Palanisamy, K. / Wautlet, B.S. / Fereshteh, M.P. / Lippy, J. / Tebben, A.J. / Sheriff, S. / Ruzanov, M. / Yan, C. / Gupta, A. / Gupta, A.K. / Vetrichelvan, M. / Mathur, A. / Gelman, M. / Singh, R. / Kinsella, T. / Murtaza, A. / Fargnoli, J. / Vite, G. / Borzilleri, R.M.
History
DepositionNov 19, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 5, 2020Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2020Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2May 12, 2021Group: Structure summary / Category: pdbx_deposit_group / Item: _pdbx_deposit_group.group_type
Revision 1.3Nov 17, 2021Group: Database references / Structure summary / Category: database_2 / pdbx_deposit_group
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_deposit_group.group_description / _pdbx_deposit_group.group_title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: TGF-beta receptor type-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,6403
Polymers35,1651
Non-polymers4752
Water3,927218
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.730, 78.110, 90.470
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein TGF-beta receptor type-1 / TGFR-1 / Activin A receptor type II-like protein kinase of 53kD / Activin receptor-like kinase 5 / ...TGFR-1 / Activin A receptor type II-like protein kinase of 53kD / Activin receptor-like kinase 5 / ALK5 / Serine/threonine-protein kinase receptor R4 / SKR4 / TGF-beta type I receptor / Transforming growth factor-beta receptor type I / TbetaR-I


Mass: 35165.473 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, UNP RESIDUES 200-503 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TGFBR1, ALK5, SKR4 / Plasmid: PFASTBAC1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P36897, receptor protein serine/threonine kinase
#2: Chemical ChemComp-QMV / 6-[4-(3-chloro-4-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazol-5-yl]imidazo[1,2-b]pyridazine-3-carbonitrile


Mass: 382.779 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H12ClFN6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C3H8O3
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 218 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.1 Å3/Da / Density % sol: 41.33 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.6 / Details: 23%(w/v) PEG3350, 3%(v/v) glcyerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 8, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.67→78.11 Å / Num. obs: 35314 / % possible obs: 100 % / Observed criterion σ(I): 0 / Redundancy: 6.5 % / Biso Wilson estimate: 20.09 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.109 / Rpim(I) all: 0.046 / Rrim(I) all: 0.118 / Rsym value: 0.1 / Net I/σ(I): 11.5 / Num. measured all: 230437
Reflection shellResolution: 1.67→1.76 Å / Redundancy: 6.7 % / Rmerge(I) obs: 0.857 / Mean I/σ(I) obs: 2.2 / Num. measured all: 34127 / Num. unique all: 5078 / CC1/2: 0.759 / Rpim(I) all: 0.353 / Rrim(I) all: 0.928 / Rsym value: 0.793 / Net I/σ(I) obs: 2.2 / Rejects: 0 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.5.31data scaling
AMoREphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TZM

3tzm


Resolution: 1.67→22.87 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.935 / SU R Cruickshank DPI: 0.098 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.103 / SU Rfree Blow DPI: 0.098 / SU Rfree Cruickshank DPI: 0.095
RfactorNum. reflection% reflectionSelection details
Rfree0.206 1723 4.92 %RANDOM
Rwork0.177 ---
obs0.178 35047 100 %-
Displacement parametersBiso max: 114.64 Å2 / Biso mean: 22.48 Å2 / Biso min: 7.63 Å2
Baniso -1Baniso -2Baniso -3
1-1.6848 Å20 Å20 Å2
2---4.2499 Å20 Å2
3---2.5651 Å2
Refine analyzeLuzzati coordinate error obs: 0.21 Å
Refinement stepCycle: final / Resolution: 1.67→22.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2422 0 33 218 2673
Biso mean--22.04 28.98 -
Num. residues----306
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d904SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes57HARMONIC2
X-RAY DIFFRACTIONt_gen_planes413HARMONIC5
X-RAY DIFFRACTIONt_it2556HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion326SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact3228SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2556HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3471HARMONIC20.99
X-RAY DIFFRACTIONt_omega_torsion3.6
X-RAY DIFFRACTIONt_other_torsion15.12
LS refinement shellResolution: 1.67→1.72 Å / Total num. of bins used: 18
RfactorNum. reflection% reflection
Rfree0.2403 127 4.55 %
Rwork0.2123 2665 -
all0.2136 2792 -
obs--100 %

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